9alpha, 21-dihalopregnanes and process



90:,21-DIHALOPREGNANES AND PROCESS Josef Fried and Josef E. Herz, NewBrunswick, N. L, as-

signors to Olin Mathieson Chemical Corporation, New York, N. Y., acorporation of Virginia No Drawing. Application June 4, 1954, Serial No.434,672

9 (Ilaims. (Cl. 260-397.45)

substituent, and of (H) certain compounds useful themselves asphysiologically-active steroids and in the preparation of otherphysiologically-active steroid derivatives.

T he process of this invention essentially comprises (a) converting anlla,2l-dihydroxy steroid of the pregnane series into the corresponding1la,2l-di(alkanesulfonyloxy) or ila-EllitllflC-SlllfOIlYlOXY-Zl-ChlOlOderivatives thereof, (b) converting the latter into the corresponding A-2l-bromo, chloro, or unsubstituted derivative, (c) converting saidA901) compound into the corresponding 9a-bronio or chloro, llfi-hydroxyderivative, (d) converting said 9a-bromo or chloro compound to thecorresponding 95,115-oxido, 21-acetoxy or to the 95,11,8-oxido,21-chloro derivative, and (e) converting said 9/3, lie-oxidederivative to the corresponding 9a-halo,11,6- hydroxy compound (e. g.9a-fluorohydrocortisone acetate). The A -21-bromo derivative formed instep (b) may be converted to the corresponding A ,2lacetoxy derivative.

The compounds of this invention comprise: (A) l la,21-di(alkanesulfonyloxy)- and Ila-alkanesulfonyloxy,2l chloro steroids of thepregnane series; (B) A ),21-bromo and chloro steroids of the pregnaneseries; (C) 9a-bromo or chloro, l1;3-hydroxy,21-bromo steroids of thepregnane series; (D) 9B,ll/3-oxido,2l-

chloro steroids of the pregnane series; and (E) 9oL-halo,-

ilfi-hydroxyJl-chloro steroids of the pregnane series.

For a clearer understanding of the foregoing general and followingdetailed description of one of the related processes of this invention,reference is made to the following schematic analysis:

nited States Patent wherein the 4,5 position is double-bonded orsaturated (the 4,5-double-bonded steroids are preferred), and wherein Ris hydrogen, R is hydroxy, or together R and R is oxo (keto) or a groupconvertible thereto by hydrolysis (e. g. acetal), R and R as oxo beingpreferred; Z is hydrogen or a-hydroxy; R is an alkanesulfonyl radical,particularly a lower alkane sulfonyl such as methanesulfonyl,ethanesulfonyl, hexanesulfonyl, etc., and is preferably methanesulfonyl;X is chloro, bromo, or iodo; l is R"O or chloro; Me is a metal, such asan alkali metal or an alkaline earth metal, the halogen salt of which issoluble in the solvent employed in the indicated reaction, preferably analkali metal, such as sodium or lithium; Y is hydrogen, bromo, orchloro; R"X is an N-bromamide (including imide) of a carboxylic acid(including derivatives), an N-chloramide (including imide) of acarboxylic acid (including derivatives), dibromodimethylhydantoin, ordichlorodimethylhydantoin; X is bromo or chloro; Y is acetoxy or chloro;and X" is a halo (fluoro, chloro, bromo, or iodo).

Compounds suitable as initial reactants in the process of this inventionset out in the foregoing schematic analysis include compound epi-F (A-pregnene-11ot,17a,21- triol-3,20-dione), epi-corticosterone (A-pregnene-lla,2ldi0l-3,20-dione) 1 la,17a,21-trihydroxy-pregnane-3,20-dione, 11a,21-dihydroxypregnane-3,20-dione etc. Thesecompounds are reacted with alkanesulfonyl halides (sulfonyl chloridesare preferred but other halides such as bromides and iodides may beused). Although any alkanesulfonyl chloride may be used, the alkanegroup is preferably a lower alkane, methanesulfonyl chloride (mesylchloride) being particularly preferred. The reaction is carried out inaccordance with the general method disclosed in the U. S. application ofJosef Fried, Serial No. 417,489, filed March 10, 1954, and in thefollowing examples, by reacting the steroid and sulfonyl halide in thepresence of dry pyridine or other tertiary organic base.

This reaction results in the production of compounds A wherein thealkanesulfonyloxy radical in the Ila-position corresponds to thealkanesulfonyl halide used in the reaction and the radical in the2l-position also corresponds to the alkanesulfonyloxy radical if Z isa-hydroxy, and is a mixture of steroids having the corresponding21-alkanesulfonyloxy radical and steroids having a 21- chloro radical ifZ is hydrogen.

Compounds A are then reacted with a metal halide (MeX) wherein MeX is asabove-defined. Particularly preferred metal halides are lithiumchloride, lithium bromide and sodium iodide.

Such solvents include the lower alkanoic acids (particularly glacialacetic acid), certain alcohols, and ketones.

This reaction results in the production of compounds B wherein the21-substituent is: bromine when a metal bromide is used; chlorine when ametal chloride is used; and hydrogen when a metal iodide isused (theintermediately formed 2l-iodo derivative having been reduced).

Compounds B are then reacted with RX', wherein R"X is asabove-defined,and is pre'f'rziblyN-bromoacetamide, N-bromosuccinimide,N-chloroacetarnide, N- chlorosuccinimide,- dibromodimethyl hydant'oin,or dichlorodimethyl hydantoin, in accordance withth e-me thod disclosedin the copending applications of Fried, Serial No. 417,489, filed Marchl0, 1954, and Fried et al., Serial No." 429,108, filedMay 11, 1954. Asdisclosed in those applications, the conversion is"preferably effectedin' the' presence 'of 'perchloric acid or other relatively strongacids;This reaction produces compounds C hav ing a9bp-chloro orbromosubstituent and an l lfi-hydroxy radical CompoundsC firemen reacted withalkali metal ac-' et'ate's suchas' potassium acetate, in a suitablesolvent suchas alcohols, lower alkanoic'acids, or ketones (preferably inan alkanol such as ethanol) as "described in the aforen'ientioned"application Serial No. 417,489

By this-reaction, compounds D are 'formed having a 913,-1113-oxidoradical, and'a 2l-substituent which is: hydrogenwhen the 2l-substitu'entof compounds C is hydrogen; acetoxy, when 'the2l-substituent ofcompounds C is bromo; and'chloro, when the -2l-substituent of compoundsC is 'chloro; Infthe case where the i 21 -substituent of compounds C ischlorog' by-reacting compounds C in the presence of analkali metaliodide (e. g. potassium iodide) as well as the alkali metal acetate-(e.'g.' potassium acetate), the 2l-substituent"in compounds-D obtained.is an acetoxy rather than a-cl'rlo'ro radical.

Compounds D 'arethen reacted with hydrogen halide (i. eI'-hydrofluoric;hydrochloric,"hydrobromic, or hydro io'di'c'acid) in a"suita'blesolventtei g" chloroform) as diS- closed in theaforementionedapplication Serial No. 417,-' 489: By this reaction;compounds are formed having a '9ot-halo and l1l3-hydr0xy radical and-aZl-Substituent corresp'onding tothe substituent' in compounds D.- Theprocess of th-isinvention is described' indet'ail inthe followingschematic analysis andeiramples employing compound epi-F" as a"startingrnaterial, but is -'of course not limited tliei 'to C HEOSOICH} omciEXAMPLE 1 A -pregrzeneJ10:,17a,21-tri0l-3,2O-di0ne 110:,21 dimesylate(I) (epi-F 11oc,21-dimesylate) To a solution of 10 gfepi-F in 110 ml.anhydrous pyridine is added at '0C. (all temperatures givenhereinafter'being'in centigrade) '-'a"solution of 6.6 ml.methanesulfonyl chloride in- 10ml. chloroform; The reaction mixtureisallowedtoremain at 0 for fifteen hours, after which 1 g. of ice is-added. After an additional onehalf hour at O, thernixture is'concentrated in vacuo to a small volume. The resulting residue is takenup in chloroform and water, and the'chloroform solution is washed withcold dilute hydrochloric acid, dilute sodium bicarbonate solution; andfinally 'with water. The chloroform" solution is then dried over 7sodium sulfate and evaporated'to dryness in vacuo; The crystallineresidue (about 12.4 g) is recrystallized from ethanol, yielding theanalytically pure dimesylate, having the following'properties: Mi P.about162" (doc); [a] ]97 (-c,0.98 in dioxane); analysis [calculated forCasi-1340982 (502.62): C, 53.26, H; 6.60; 5, 12.36; found(approximately): 6, 53.42; I-I;-6.29; S, 11. 00].

EXAMPLE 2 21wh-lordN regneneJ1 bz-ol-3g20-dioize 11 oL-mesylate' aizdep'icofficosterone dimesylate To a solution of 164 mg. ofepicorticosterone in 2 ml. of'dry'pyridine isadded at O 'C. a solutionof 11 ml. of methanesulfonyl chloride in 1 ml. of chloroform and themixture is'allowed to stand in the refrigerator overnight. The excessmesylchloi'ide is destroyed with ice and the mixture-worked"up asdescribed in Example 1. About 176mg. of crystalline material isobtained, which after two recrystallizations fronracetone-ether givesabout 63 mg. of 2l-chloro A pregnane-1la-ol-3,20-dione'11mmesylate,156-157 C. (d ed), [a]D+137 (c, 0.34 in chloroform);

A'nalysis.-Calcd. for CazHsrOsSCl (442.99): C, 59.65; H, 7. 05; S, 7.24;Cl, 8.00. Found: C, 59.19; H, 6.91; S, 8.52; Cl, 7.78. v

The material recovered from the mother liquid constitutes theHail-dimesylate of epicorticosterone.

The-following three examples illustrate the preparation of A-pregnenederivatives of this invention.

EXAMPLE 3 21-br0m0-A pfegnadiened7a-0l-3,20-dione u A solution of mg. ofepi-F- dimesylate (I) (prepared as in Example I), 25 mg. of anhydrouspotassium acetate and 200 mg. of anhydrous lithium bromide in 6 ml.ofglacialacetic acid is refluxed'with the exclusion of moisture forl'hour. The slightly colored solution is then evaporated to dryness invacuo. The residue is taken up in chloroform and water and washed withNaHCOs and again with water. The dried chloroform solution isevaporatedleaving 'a'crystalline residue which weighs about-'76 mg.Recrystallization from acetone gives prisms M. P. 198-199 (dec.), about48 mg; M. P.

191-492 (dec.), about 13 mg., [a]D+l06 (c; 0.56 in chloroform) yield:about 75%.

A232? 239 my.( 6 16,400), 280 my.( 6 =995),

Analysis.Calcd. for C21H27O3Br (407.35): C. 61.91; H, 6.68; Br, 19.62.Found: C, 61.79; H, 6.73; Br, 19.59.

EXAMPLE 4 A -pregnadiene-I7a,21-diol-3,20-di0ne 21-acetate 14 mg. of A-pregnadiene-17a,21-diol-3,20-dione 21- M acetate, disclosed in theaforementioned application Serial No. 417,489.

EXAMPLE 5 21-chl0r0- M -pregnadiene-J 7a-ol-3,20-di0ne (III A solutionof 100 mg. of epi-F dimesylate (I), mg. of anhydrous potassium acetateand 200 mg. of lithium chloride in 6 ml. of glacial acetic acid isrefluxed for 1 hour with the exclusion of moisture. The acetic acid isremoved in vacuo, the residue taken up in chloroform and water and thechloroform solution washed with bicarbonate solution and again withWater. The chloroform solution is dried over sodium sulfate and onevaporalion leaves about 68 mg. of a crystalline residue.Recrystallization from acetone yields about 49 mg. (68%) M. P. 242-243"(dec.), [a]n+120 (c, 0.36 in chloroform),

Analysis.-Calcd. for Carl-1210301 (362.89): C, 69.50; H, 7.50; Cl, 9.77.Found: C, 69.94; H, 7.72; CI, 9.75.

EXAMPLE 6 A -pregnadienel 7a-0l-3,20-di0ne (IV) A solution of 100 mg. ofepi-F dimesylate (I), 25 mg. of anhydrous potassium acetate and 400 mg.of sodium iodide in 6 ml. of glacial acetic acid is refluxed forminutes. The solution soon assumes the brown iodine color. At the end ofthe reaction time the acetic acid is removed in vacuo, the residue takenup in water and chloroform and the chloroform solution washed withsodium sulfite solution and water. After drying over sodium sulfate andevaporation of the solvent in vacuo, about 63 mg. of crystals (93%) areobtained. Recrystallization from acetone yields about 43 mg. of pure A-pregnadiene-17ot-ol-3,20-dione, M. P. 216-217", [a]D-{-63 (c, 0.39 inchloroform). Infrared comparison shows identity with an authenticsample.

Following the procedure of Example 6 with the 21- chloro-llot-hydroxyprogesterone lla-mesylate of Example 2 substituted for epi-Fdimesylate, 21-chloro- A pregnadiene-3,20,dione is produced.

The following examples illustrate the preparation of the9ot-halo,11B-hydroxy pregnane derivatives in accordance with thisinvention:

EXAMPLE 7 To a solution of 250 mg. of 21'bromo- A-pregnadiene-l7a-ol-3,20-dione (II) (M. P. 192193) in 25 ml. of puredioxane and 2.5 ml. water is added 125 mg. of N-brornacetamide and 1.5ml. of 1 N HClOr. The mixture is stirred at room temperature and after 1hour and 30 minutes the excess N-bromoacetamide is destroyed with NazSOasolution. The reaction mixture is diluted with an equal volume ofchloroform, the resulting aqueous layer separated off and thechloroform-dioxane layer washed with bicarbonate and Water. After dryingand evaporation of the solvents in vacuo an oil is obtained whichcrystallized on addition of ether. The crystals are leached with moreether, and dried, M. P. 148150 (dec.), about 237 mg. (77%). A sample isrecrystallized twice from acetone-ether, M. P. 169-170" (dec.), teln+l6l(c, 0.39 in EtOH),

A523? 242 111M e=l7,400), 3.0112, 5.79 6.10

Analysis.--Calcd. for C21H2804B1'2 (504.27): C, 50.02; H, 5.60; Br,31.70. Found: C, 50.68; H, 5.88; Br, 30.09.

EXAMPLE 8 9st bromo 1 chloro A pregnene-I1,8,17a-di0l-3,20- aione (VI)[9a br0m0,21 chime-11 3,]7a-dihydr0xyprogesterone] To a solution of 100mg. of 21-chloro-A -preguadiene-17a-0l-3,20-dione (III) in 10 ml. ofdioxane and 1 ml. of water is added 56 mg. of N-bromoacetamide and 0.65ml. of 1 N HClOa. The solution was stirred for 1 /2 hours and the excessN-bromoacetamide is destroyed by the addition of a dilute sodium sulfitesolution. After the addition of 30 ml. of chloroform the resultinglayers are separated and the chloroform-dioxane phase washed with water,NaHCOz and again with Water, dried over sodium sulfate and evaporated invacuo, An oil is obtained which crystallized on addition ofacetoneether. About 78 mg. of crystals of M. P. 2l2-15 (dec.) areobtained. The mother liquors contain an additional 47 mg. The analyticalsample is recrystallized from acetone-ether, M. P. 218-219 (dec.), [a]+175 (c, 0.36 in chloroform),

EXAMPLE 9 9a-br0m0-A -pregnene-11B,17a-di0l-3,2t0-di0ne (IX) 330 mg. ofA -pregnadiene-17a-ol-3,20-dione (IV) is treated with 200 mg.N-bromoacetamide, and the reacmax.

C: Found: C, 54.83; H, 6.02;

tion mixture worked up as described in Example 7. The

9a-chloro-M-pregnene-11,8,17a-di0l-3,20-dione (X) [9a.-chloro-I15,17a-dihydr0xy-pr0gester0nel] 110 mg. of A-pregnadiene17ct-ol-3,20-dione (IV) is dissolved in 20 ml. of dioxaneand 2 ml. of water is added. To the resulting solution is added mg. ofN,N-dichloro-dimethylhydantoin and 1 ml. of l N per chloric acid and themixture is allowed to stand at room 7 temperature-for Gil-minutes;Dilute 'aqueous sodium sulfife" solution "is -addd to destroy residual"N,N-dichloro'- dim'ethyl"hydantoiriand-the mixture isdiluted'with25 Imll of chl'oroform which causes separation into-' two layers: Thechloroforrn-dioXanephase is separated off, washed with water; sodiumbicarbonateand again with water, dried over sodiiim sulfate andevaporated to dry nessidvacuo? The resulting residue (about128'rng.')

on recrystallization from acetone-chloroform-hexane,

yields pure 9a-chlor0-115,17ii-dihydroxyprogesterone, M. P. about242-243 C. (dec.).' The compound is identified by infrared spectrum andmixture melting point comparison with an authentic sample. Yield ofabout 58mg.

If 2l-chloro-A -pregnadiene3,ZO-dione is substituted forcompoundIV inExamples 9 and 10, 2l-chloro- 9|z-brorno-A -pregnene-11,3rol-3,2O-dione[2l-Chl01'O-9abromo-llfi-hydroxyprogesterone] and 9a,2l-dichloro-Apregnene-l 1,8-01-3 ,20-dione [9a,2l-dlChlOIO-l 1fi-hydroxyprogesterone] are formed, respectively.

The'following examplesillustrate' the preparation of- 9l3,1lB-oxidopregnane derivatives in accordance with this invention:

EXAMPLE 11' 9B,] 1 fi-bxid-A -pregnene-I 711,21 -diol-3 ,ZO-dioneZZ-acetate (XI) A solution of 180mg; of 91,2l-dibromo-A -pregnene17a,116-dio1-3,20'-di0ne (V) and 500 mg.'of anhydrous potassium acetatein 25ml. of absolute alcohol is re fluxed for 2 /2 hrs; The ethanol-isremoved in vacuo and the :resulting residue takenup'in water andchloroform and the chlc'iroform'solution washed freerof salts.Afterdrying and evaporation of the chloroform about 155 mg;

of crystallinematerial are. obtained. Recrystallization fromacetone-ether affords about 50 mg. of purematerial Mi P.*2()7-2 O9and'about 17mg. of M. P. 195496 (47%), [a] ]30 c; 0.41 in chloroform);

A -pregnene 17u;2l-diol3,20 dione 2'l-acetate' (cf; the aforementioned"application Serial No." 417,409)

EXAMPLE 12 The process of Examplellis repeated with 9a-bromo-21-chloro-A -pregnene-11,8,17a-diol,3,2O-dione (VI) substituted for911,21-dibromoA =pregnene-17a,l l B-diol-3,20- dion'e- (V). Thesolutionof VI. and potassium acetate in absolute alcohol is refluxed for 20minutes rather than 2 hours. Isolation and purification in accordancewith the methodof Example 11 yields 21'-chloro-9fi;'1l[3-"oxido- Apregnene17a-ol 3;20 dione;-

the method disclosed 1 in the aforementioned" application' SerialNumber: 417 ,4893

Infrared comparison showed identity with authentic 9fl,11B-'oxido---3,20-dione (XII) similarly may"beconverted to th'e corresponding21-chloro-9a-halo-Abpregnene-11,8,l7oc-di0h 3,20-dione as well as2l-chloro-9e-halo-A -pregnene-171iol-3,1l,20-trio'ne, which'are newsteroids having mineralo-- and iglucocorticoid Factiv'ity;and!2l1-chloro-.9,B,1 l fi-oxido- A. -pregnene 3,*20-dione may also beconverted to the corresponding 21-chloro-9a-halo-A -pregnene-1Idol-3,20-dione as well as 2l-chloro-9d=halo-A -pregnene-3,11,20- trione, whichare new steroids having mineralocorticoid activity.

The invention maybe otherwise embodied within thescope of the appendedclaims.

We claim:

1. A compound selected from. the groupconsisting ofz' CHZY and

wherein R is hydrogen, R is hydroxy and together R and R is keto; Z is aradical selected from the group consisting of hydrogen and hydroxy; X isa halogen radical; and Y is a radical selected from the group consistingof bromine and chlorine.

2. 21 chloro 9a halo A pregnene 1113,1711 diol-3',20-dione.

3'.- 21-bromo-9a-X-A -pregnene-11fi,17a-dio1-3,20-dione, Wherein'X'isahalogen of atomic weight greater than andless'than 85.

5. The process for producing a 9a-halo,11fl-hydroxysteroid ofthepregnane series, which comprises reacting a 2l-bromo,A -steroid of"the pregnane series with a hydroxyhalogenating agent, selected from thegroup con sisting of a hydroxychlorinating agent'and ahydroxybrominating'agent, to form a 21-bromo,1lfi hydroxy,9ahalo steroidwherein the halo radical is selected from the group consisting ofbromine and chlorine, and recovering said 9'a-h'alo,11 8-hydroxysteroid.

6. The process for producing a 9ot-halo-1l 8-hydroxysteroid of thepregnane series, which comprises reacting a 2l-chloro',A -steroid of thepregnane series with a hydroxyhalogenating agent selected from'the groupcon sisting of a hydroxychlorinating agent" and a hydroxybrominatingagent, to form a 2l-chloro,1lB-hydroxy,9a-

halosteroid, wherein the halo radical is selected from the groupconsisting ofbromine and chlorine, and recovering said-9a-halo;11e-hydroxy steroid.

7. The-process for producinga 2l-chloro,9a-halo,11 8

hydroxy-steroid of: the pregnane series, which comprises reactingra9p,11;i.-oxido-21-chloro steroid. of the:preg-- nane serieswi'th ahydrogenhalide, and-recovering: the- 21-chloro-9u-ha1o;11p=hydroxy-'steroid formed.

9 8. 9a.,21 dibromo A pregnene 11p,17a diol 2,409,798 3,20-dione.2,640,838 9. 9a bromo 21 chloro A pregnene 115,174 2,656,365diol-3,20-dione. 2,684,968

5 References Cited in the file of this patent UNITED STATES PATENTS2,183,589 Reichstein Dec. 19, 1939 10 Reichstein Oct. 22, 1946 WendlerJune 2, 1953 Miescher Oct. 20, 1953 Bergstrom July 27, 1954

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: